U.S. patent application number 10/207726 was filed with the patent office on 2004-01-29 for oral care compositions comprising tropolone compounds and essential oils and methods of using the same.
Invention is credited to Arvanitis, Georgia, Berardini, Michael, Finnegan, Marybeth, Pan, Pauline, Soshinsky, Andre.
Application Number | 20040018154 10/207726 |
Document ID | / |
Family ID | 30770520 |
Filed Date | 2004-01-29 |
United States Patent
Application |
20040018154 |
Kind Code |
A1 |
Pan, Pauline ; et
al. |
January 29, 2004 |
ORAL CARE COMPOSITIONS COMPRISING TROPOLONE COMPOUNDS AND ESSENTIAL
OILS AND METHODS OF USING THE SAME
Abstract
The present invention relates to oral care compositions suitable
for preventing or treating diseases or conditions of the oral
cavity in warm-blooded animals including humans, comprising an oral
care effective amount of at least one tropolone compound in
combination with at least one essential oil, and a pharmaceutically
acceptable oral carrier. This invention further relates to a method
for preventing or treating diseases or conditions of the oral
cavity in warm-blooded animals including humans, by applying an
oral care effective amount of the oral care composition to the oral
cavity.
Inventors: |
Pan, Pauline; (Denville,
NJ) ; Finnegan, Marybeth; (Hillsborough, NJ) ;
Soshinsky, Andre; (Randolph, NJ) ; Arvanitis,
Georgia; (Ewing, NJ) ; Berardini, Michael;
(Ewing, NJ) |
Correspondence
Address: |
WATOV & KIPNES, P.C.
P.O. Box 247
Princeton Junction
NJ
08550
US
|
Family ID: |
30770520 |
Appl. No.: |
10/207726 |
Filed: |
July 29, 2002 |
Current U.S.
Class: |
424/49 |
Current CPC
Class: |
A61K 8/35 20130101; A61Q
11/00 20130101 |
Class at
Publication: |
424/49 |
International
Class: |
A61K 007/16 |
Claims
What is claimed is:
1. An oral care composition comprising: (a) an oral care effective
amount of at least one compound of Formula (I) 9wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each independently
selected from the group consisting of hydrogen, hydroxy, an alkyl
group, a hydroxyalkyl group, an alkoxyalkyl group, an alkylene
group, an alkenylene group, an alkaryl group, an alkcycloalkyl
group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl
group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group
optionally substituted with 1 to 3 halogens, an aromatic group
optionally substituted with 1 to 3 halogens, and a carbonyl group,
and pharmaceutically acceptable salts thereof; (b) at least one
essential oil; and (c) a pharmaceutically acceptable oral
carrier.
2. The compound of claim 1 wherein the alkyl group has 1 to 6
carbon atoms, the hydroxyalkyl group has 1 to 6 carbon atoms and
the alkoxy portion and the alkyl portion of the alkoxyalkyl group
each have 1 to 6 carbon atoms.
3. The oral care composition of claim 1 wherein the oral effective
amount of the compound of Formula (I) is from about 0.001% to 10%
by weight based on the total weight of the oral care
composition.
4. The oral care composition of claim 3 wherein the oral effective
amount of the compound of Formula (I) is from about 0.01% to 5.0%
by weight.
5. The oral care composition of claim 4 wherein the oral effective
amount of the compound of Formula (I) is from about 0.1% to 2.0% by
weight.
6. The oral care composition of claim 1 wherein the at least one
essential oil selected from the group consisting of thymol,
menthol, methyl salicylate (wintergreen oil), eucalyptol,
carvacrol, camphor, anethole, carvone, eugenol, isoeugenol,
limonene, osimen, n-decyl alcohol, citronel, a-salpineol, methyl
acetate, citronellyl acetate, methyl eugenol, cineol, linalool,
ethyl linalaol, safrola vanillin, spearmint oil, peppermint oil,
lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil,
pimento oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise
oil, bay oil, benzaldehyde, bergamot oil, bitter almond,
chlorothymol, cinnamic aldehyde, citronella oil, clove oil, coal
tar, eucalyptus oil, guaiacol, lavender oil, mustard oil, phenol,
phenyl salicylate, pine oil, pine needle oil, sassafras oil, spike
lavender oil, storax, thyme oil, tolu balsam, terpentine oil, clove
oil and combinations thereof.
7. The oral care composition of claim 6 wherein the at least one
essential oil selected from the group consisting of thymol,
eucalyptol, menthol, and methyl salicylate.
8. The oral care composition of claim 7 wherein the oral care
effective amount of thymol is from about 0.001% to 2.0% by weight
based on the total weight of the oral care composition.
9. The oral care composition of claim 8 wherein the oral care
effective amount of thymol is from about 0.01% to 0.6% by
weight.
10. The oral care compositions of claim 9 wherein the oral care
effective amount of thymol is from about 0.02% to 0.5% by
weight.
11. The oral care composition of claim 7 wherein the oral care
effective amount of eucalyptol is from about 0.001% to 2.0% by
weight based on the total weight of the oral care composition.
12. The oral care composition of claim 11 wherein the oral care
effective amount of eucalyptol is from about 0.005% to 0.5% by
weight.
13. The oral care composition of claim 12 wherein the oral care
effective amount of eucalyptol is from about 0.007% to 0.4% by
weight.
14. The oral care composition of claim 7 wherein the oral care
effective amount of methyl salicylate is from about 0.001% to 2.0%
by weight based on the total weight of the oral care
composition.
15. The oral care composition of claim 14 wherein the oral care
effective amount of methyl salicylate is from about 0.004% to 0.6%
by weight.
16. The oral care composition of claim 15 wherein the oral care
effective amount of methyl salicylate is from about 0.01% to 0.6%
by weight.
17. The oral care composition of claim 7 wherein the oral care
effective amount of menthol is from about 0.001% to 2.0% by weight
based on the total weight of the oral care composition.
18. The oral care composition of claim 17 wherein the oral care
effective amount of menthol is from about 0.01% to 0.7% by
weight.
19. The oral care composition of claim 18 wherein the oral care
effective amount of menthol is from about 0.01% to 0.6% by
weight.
20. The oral care composition of claim 1 wherein the at least one
compound of Formula (I) is selected from the group consisting of
4-methyl-7-hydroxymethyltropolone,
4-methyl-7-methoxymethyltropolone, 4,7-dimethyltropolone,
7-methyl-4-isopropyltropolone, 7-hexyl-4-isopropyltropolone,
4-t-butyltropolone, 5-t-butyltropolone, 4-isopropyltropolone,
4-methyltropolone, 7-methoxymethyl-4-isopropyltropo- lone,
7-hexloxymethyl-4-isopropyltropolone and combinations thereof.
21. The composition of claim 1 wherein the oral care effective
amount of at least one essential oil is from about 0.001% to 8.0%
by weight based on the total weight of the oral care
composition.
22. The composition of claim 7 wherein the oral care effective
amount of the at least one essential oil comprises 0.064% by weight
of thymol, 0.092% by weight of eucalyptol, 0.060% by weight of
methyl salicylate, and 0.042% by weight of menthol, each based on
the total weight of the oral care composition.
23. The composition of claim 1 further comprising an alcohol in an
amount of from about 0.01% to 70% by weight based on the total
weight of the oral care composition.
24. The composition of claim 23 wherein the amount of alcohol is
from about 0.1% to 30% by weight.
25. The composition of claim 24 wherein the alcohol is ethanol.
26. The composition of claim 7 wherein the oral care effective
amount of the compound of Formula (I) is from about 0.03% to 2% by
weight based on the total weight of the oral care composition, and
of the at least one essential oil is 0.064% by weight of thymol,
0.092% by weight of eucalyptol, 0.060% by weight of methyl
salicylate, and 0.042% by weight of menthol, each based on the
total weight of the oral care composition.
27. The oral care composition of claim 1 wherein the amount of the
at least one essential oil is from about 0.001% to 8% by weight
based on the total weight of the oral care composition.
28. A method for treating or preventing diseases or conditions of
the oral cavity in warm-blooded animals including humans,
comprising applying an oral care effective amount of the
composition of claim 1 to the oral cavity.
29. The method of claim 27 comprising applying the composition of
claim 1 in a form selected from the group consisting of
toothpastes, mouthwashes, gels, tooth powders, film forming
dentifrices, chewing gums, mouth sprays and lozenges.
Description
FIELD OF THE INVENTION
[0001] The present invention is related generally to oral care
compositions, more particularly to oral care compositions
comprising substituted tropolone compounds and essential oils, and
methods of using the same for oral care.
BACKGROUND OF THE INVENTION
[0002] Oral malodor, plaque, gingivitis, periodontal disease, and
discoloration of the teeth, are all undesirable conditions that
affect many people. First malodor of the oral cavity also known as
halitosis or bad breath, has been broadly estimated to afflict 20
to 90 million individuals in the US. It is generally believed that
the presence of anaerobic bacteria, especially gram-negative
anaerobic bacteria, in the mouth contributes to this condition.
Other oral conditions caused by microorganisms include periodontal
disease, tooth decay, inflammation and the like.
[0003] Periodontal disease is a major cause of tooth loss in
adults, and can manifest itself in people as young as age 12.
Periodontal disease affects the periodontum, which is the investing
and supporting tissues surrounding a tooth (i.e., the periodontal
ligament, the gingiva, and the alveolar bone). Gingivitis and
periodontatitis are disorders of the gingiva and the deeper
periodontal tissues, respectively. Periodontal disease is generally
associated with the accumulation of plaque on the teeth. The teeth
are coated with a salivary proteinaceous material (pellicle) and
thereafter streptococci adhere to this coating. Gingivitis is
generally caused by dental plaque, and periodontatitis is caused by
the infection spreading to the periodontal pocket or space between
the gingival and the tooth root.
[0004] Many of the current oral care compositions including
toothpastes, mouthwashes, rinses and tooth gels are formulated to
clean the oral cavity and kill pathogenic microbes. Such oral care
compositions are typically formulated with one or more
antimicrobial agents to suppress the microorganisms that contribute
both to the initiation and progression of oral malodor, periodontal
disease and other undesirable oral conditions. Current oral care
compositions comprise antimicrobial agents and are formulated to
maximize the kinetics of the antimicrobial agent. The antimicrobial
agents are dissolved to provide effective prevention of bad breath,
eradication of oral microbes, and penetration, reduction, and
elimination of plaque and gingivitis.
[0005] One well-known antiseptic agent is thymol, also known as an
essential oil, which is utilized for its antimicrobial activity in
a range of oral care preparations. In particular, thymol has been
utilized in oral hygiene compositions such as mouthwashes in
sufficient quantities to provide desired beneficial therapeutic
effects. LISTERINE.RTM. Brand mouth rinse is a well-known
antiseptic mouthwash that has been used by millions of people for
over one hundred years and has been proven effective in killing
microbes in the oral cavity that are responsible for plaque,
gingivitis, and bad breath. Thymol and other essential oils, such
as methyl salicylate, menthol, and eucalyptol, are active
ingredients (e.g., antimicrobial agents) in antiseptic mouth rinses
such as LISTERINE.RTM.. Even in small amounts, these essential oils
are effective antimicrobial agents. Without being restricted to any
specific theory, it is believed that the efficacy and taste of
antiseptic mouthwashes such as LISTERINE.RTM. may be due to the
dissolution and delivery kinetics of these four active agents.
[0006] There is still a need to provide efficacious oral care
compounds and oral care compositions such as mouthwashes or rinses
containing the same having favorable antimicrobial kinetics while
exhibiting chemical stability and solubility favorable for
efficient delivery and antiseptic effectiveness. There is still a
need to provide oral care compositions and compounds that are
effective for the prevention or treatment of diseases and
conditions of the oral cavity in warm-blooded animals including
humans by eliminating or suppressing the presence of pathogenic
oral microorganisms responsible for plaque, gingivitis and other
undesirable oral conditions in the oral cavity.
SUMMARY OF THE INVENTION
[0007] The present invention relates to oral care compositions and
methods of using the same for preventing or treating diseases or
conditions of the oral cavity in warm-blooded animals including
humans. Generally, the oral care composition comprises substituted
tropolone compounds in combination with one or more essential oils
in amounts effective for suppressing or eliminating the presence of
harmful pathogenic oral microorganisms in the oral cavity, The oral
care compositions provide a high level of antimicrobial kinetics
and efficacy useful for preventing, among others, plaque, gum
disease, and oral malodor. In addition, the oral care composition
can be formulated into a range of oral care products including, but
not limited to, toothpastes, tooth gels, tooth powders,
mouthwashes, lozenges, chewing gums, tooth strips, dental floss,
orally consumable film and mouth spray.
[0008] In one particular aspect of the present invention, there is
provided an oral care composition comprising:
[0009] (a) an oral care effective amount of at least one compound
of Formula (I) 1
[0010] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
each independently selected from the group consisting of hydrogen,
hydroxy, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl
group, an alkylene group, an alkenylene group, an alkaryl group, an
alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl
group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an
aliphatic group optionally substituted with 1 to 3 halogens, an
aromatic group optionally substituted with 1 to 3 halogens and a
carbonyl group, and isomers and pharmaceutically acceptable salts
thereof;
[0011] (b) at least one essential oil; and
[0012] (c) a pharmaceutically acceptable oral carrier.
[0013] In a preferred embodiment of the present invention, the oral
care composition comprises an oral care effective amount of at
least one compound of Formula (I) wherein R.sub.2, R.sub.3, and
R.sub.5 are each independently selected from the group consisting
of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl
group having 1 to 6 carbons, and an alkoxyalkyl group wherein the
"alkoxy" portion and the "alkyl" portion each have from 1 to 6
carbons, and R.sub.1 and R.sub.4 are each hydrogen.
[0014] Preferably the essential oil is selected from the group
consisting of thymol, eucalyptol, menthol, methyl salicylate, and
combinations thereof.
[0015] In another aspect of the present invention, there is
provided a method for preventing or treating diseases or conditions
of the oral cavity, comprising administering an oral care effective
amount of the oral care composition of the present invention to a
warm-blooded animal including humans.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention is directed to oral care compositions
with antimicrobial efficacy against microorganisms, particularly
oral microorganisms responsible for producing undesirable diseases
or conditions in the oral cavity, including oral malodor, plaque
build-up, and the like, and the resulting tooth and gum diseases
that may follow. The oral care compositions may be in a form
selected from, for example, mouthwashes, toothpastes, tooth
powders, dental creams, dental flosses, liquids, gels, chewing
gums, liquid center filled gums, mints, lozenges, orally consumable
films and the like. One preferred aspect of the present invention
is directed to an oral care composition containing an effective
amount of at least one substituted tropolone compound having
antimicrobial activity in combination with one or more essential
oils. In a particularly preferred aspect of the present invention,
there is provided an oral care composition, preferably a mouthwash,
containing an effective amount of at least one substituted
tropolone compound in combination with at least one essential
oil.
[0017] Essential oils are volatile aromatic oils which may be
synthetic or may be derived from plants by distillation, expression
or extraction, and which usually carry the odor or flavor of the
plant from which they are obtained. In the oral care composition of
the present invention, the essential oils provide antiseptic
activity. Some of these essential oils also act as flavoring
agents. The essential oils of this invention include but are not
limited to thymol, menthol, methyl salicylate (wintergreen oil),
eucalyptol, carvacrol, camphor, anethole, carvone, eugenol,
isoeugenol, limonene, osimen, n-decyl alcohol, citronel,
a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol,
cineol, linalool, ethyl linalaol, safrola vanillin, spearmint oil,
peppermint oil, lemon oil, orange oil, sage oil, rosemary oil,
cinnamon oil, pimento oil, laurel oil, cedar leaf oil, gerianol,
verbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter
almond, chlorothymol, cinnamic aldehyde, citronella oil, clove oil,
coal tar, eucalyptus oil, guaiacol, lavender oil, mustard oil,
phenol, phenyl salicylate, pine oil, pine needle oil, sassafras
oil, spike lavender oil, storax, thyme oil, tolu balsam, terpentine
oil, clove oil, and combinations thereof. Preferred essential oils
are selected from thymol, methyl salicylate, eucalyptol, menthol
and combinations thereof.
[0018] The present invention is effective for cleaning the oral
cavity and/or treating diseases and conditions of the oral cavity
including, but not limited to, gingivitis, periodontitis, oral
malodor, tooth decay, and the like. The oral care compositions of
the present invention provide a high degree of antimicrobial
efficacy against microorganisms, particularly pathogenic oral
microorganisms, including, but not limited to, Fusobacterium
nucleatum, Prevotella intermedia, Actinomyces viscosus,
Campylobacter rectus, Porphyromonas gingivalis, Streptococcus
sanguis, Streptococcus mutans, Actinobacillus, Bacteroides,
Capnocytophaga, Eikenella, Propionibacterium, and Candida albicans
responsible for oral malodor and build-up of plaque and calculus
and the resulting tooth and gum diseases that may follow.
[0019] The present invention is also directed to methods of
cleaning the oral cavity, and/or treating or preventing diseases or
conditions of the oral cavity in warm-blooded animals including
humans, by applying to the oral cavity an oral care effective
amount of the oral care composition of the present invention.
[0020] The term "diseases or conditions of the oral cavity," as
used herein, is meant to include diseases of the oral cavity
including, but not limited to, periodontal disease, gingivitis,
periodontatitis, periodontosis, adult and juvenile periodontatitis,
and other inflammatory conditions of the tissues within the oral
cavity in warm-blooded animals including humans, plus caries,
necrotizing ulcerative gingivitis, and other conditions such as
oral malodor or disagreeable mouthfeel. The compositions and
methods of treatment and oral care provided by the present
invention are particularly effective for preventing or treating
periodontal disease (gingivitis and/or periodontatitis) and oral
malodor in warm-blooded animals including humans.
[0021] In one particular aspect of the present invention, there is
provided an oral care composition comprising:
[0022] (a) an oral care effective amount of at least one compound
of Formula (I) 2
[0023] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
each independently selected from the group consisting of hydrogen,
hydroxy, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl
group, an alkylene group, an alkenylene group, an alkaryl group, an
alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl
group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an
aliphatic group optionally substituted with 1 to 3 halogens, an
aromatic group optionally substituted with 1 to 3 halogens, and a
carbonyl group, and isomers and pharmaceutically acceptable salts
thereof;
[0024] (b) at least one essential oil; and
[0025] (c) a pharmaceutically acceptable oral carrier.
[0026] In a preferred embodiment of the present invention, the oral
care composition comprises an oral care effective amount of at
least one compound of Formula (I) wherein R.sub.2, R.sub.3, and
R.sub.5 are each independently selected from the group consisting
of hydrogen, an alkyl group having 1 to 6 carbons, a hydroxyalkyl
group having 1 to 6 carbons, and an alkoxyalkyl group wherein the
"alkoxy" portion and the "alkyl" portion each have from 1 to 6
carbons, and R.sub.1 and R.sub.4 are each hydrogen.
[0027] Isomers of the compounds of Formula (I) having the desired
antimicrobial activity mixtures thereof are included in the scope
of the present invention.
[0028] In addition, hydrates and solvates with pharmaceutically
acceptable organic solvents, as well as prodrugs of the compounds
of the present invention are also encompassed by the present
invention.
[0029] In addition, compounds of Formula (I) or pharmaceutically
acceptable salts thereof may be present in the form of addition
products with water or various solvents, and these addition
products are also included in the scope of the present
invention.
[0030] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. They can be derived from a variety of organic and inorganic
cations well known in the art and include, by way of example,
sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like, and anions, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
oxalate, and the like. When the compound of the present invention
is basic, salts may be prepared from pharmaceutically acceptable
non-toxic acids, including inorganic and organic acids. Such acids
include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
Particularly preferred are citric, hydrobromic, hydrochloric,
maleic, phosphoric, sulfuric, and tartaric acids. Salts derived
from inorganic bases include aluminum, ammonium, calcium, copper,
ferric, ferrous, lithium, magnesium, manganic salts, manganous,
potassium, sodium, zinc, and the like.
[0031] Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, and basic
ion exchange resins, such as arginine, betaine, caffeine, choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like. Those skilled in the
art will recognize a wide variety of non-toxic pharmaceutically
acceptable addition salts.
[0032] The term "alkyl" refers to monovalent straight and branched
alkyl groups preferably having from about 1 to 18 carbon atoms,
more preferably from about 1 to 14 carbon atoms, and still more
preferably from about 1 to 6 carbon atoms. This term is exemplified
by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl, and the
like.
[0033] The term "alkylene" refers to divalent alkylene groups
preferably having from about 1 to 18 carbon atoms and more
preferably from about 1 to 14 carbon atoms which can be straight or
branched. The term is exemplified by groups such as methylene
(--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), the propylene
isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0034] The term "alkenylene" refers to divalent alkenylene groups
preferably having from about 2 to 18 carbon atoms and more
preferably from about 2 to 14 carbon atoms which can be straight
chain or branched and having at least 1 and preferably 1 to 2 sites
of alkenyl unsaturation. This term is exemplified by groups such as
ethenylene (--CH.dbd.CH--), the propenylene isomers (e.g.,
--CH.dbd.CHCH.sub.2-- and --C(CH.sub.3).dbd.CH-- and
--CH.dbd.C(CH.sub.3)--) and the like.
[0035] The term "alkaryl" refers to -alkylene-aryl groups
preferably having from about 1 to 18 carbon atoms in the alkylene
moiety and from about 6 to 14 in the aryl moiety. Such alkaryl
groups are exemplified by benzyl, phenethyl, and the like.
[0036] The term "alkcycloalkyl" refers to -alkylene-cycloalkyl-
groups preferably having from about 1 to 18 carbons atoms in the
alkylene moiety and from about 3 to 14 in the cycloalkyl moiety.
Such alkcycloalkyl groups are exemplified by
--CH.sub.2-cyclopropyl, --CH.sub.2-cyclopentyl,
--CH.sub.2CH.sub.2-cyclohexyl, and the like.
[0037] The term "alkoxy" refers to the group "alkyl-O--". The
alkoxy groups include, by way of example, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, and the like, preferably having from about 1 to 6 carbon
atoms. The term "alkoxyalkyl" refers to the groups
"alkyl-O-alkyl-", preferably the alkyl portion of the group has 1
to 6 carbon atoms and the alkoxy portion of the group has 1 to 6
carbon atoms.
[0038] The term "alkenyl" refers to alkenyl groups preferably
having from about 2 to 18 and more preferably having from about 2
to 14 carbon atoms and having at least 1 and preferably from 1 to 2
sites of alkenyl unsaturation. Such alkenyl groups are exemplified
by ethenyl (--CH.dbd.CH.sub.2, n-propenyl
(--CH.sub.2CH.dbd.CH.sub.2), isopropenyl
(--C(CH.sub.3).dbd.CH.sub.2), and the like.
[0039] The term "alkynyl" refers to alkynyl groups preferably
having from about 2 to 18 carbon atoms and more preferably from
about 2 to 14 carbon atoms and having at least 1 and preferably 1
to 2 sites of alkynyl unsaturation. Such alkynyl groups are
exemplified by ethynyl (--CH.ident.CH.sub.2), propargyl
(--CH.sub.2CH.ident.CH.sub.2) and the like.
[0040] The term "aryl" refers to an unsaturated aromatic
carbocyclic groups from about 6 to 18 carbon atoms having a single
ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or
anthryl). Examples of aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the individual
substituent, such aryl groups can optionally be substituted with
from 1 to 3 substituents selected from the group consisting of
alkyl, alkoxy, acyloxy, hydroxy, and the like.
[0041] The term "cycloalkyl" refers to cyclic alkyl groups of from
about 3 to 18 carbon atoms having a single cyclic ring or multiple
condensed rings which can be optionally substituted with from 1 to
3 alkyl groups. Such cycloalkyl groups include, by way of example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl,
1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and
the like, or multiple ring structures such as adamantanyl, and the
like.
[0042] The term "cycloalkenyl" refers to cyclic alkenyl groups of
from about 4 to 18 carbon atoms having a single cyclic ring and at
least one point of internal unsaturation which can be optionally
substituted with from 1 to 3 alkyl groups. Examples of suitable
cycloalkenyl groups include, for instance, cyclopent-3-enyl,
cyclohex-2-enyl, cyclooct-3-enyl, and the like.
[0043] Preferred tropolone compounds of Formula (I) for use in the
oral care compositions of the present invention include those
selected from the group consisting of
2-hydroxy-7-methyl-2,4,6-cycloheptatrien-1-one;
2-hydroxy-7-heptyl-2,4,6-cycloheptatrien-1-one;
2-hydroxy-7-(methoxymethy- l)-2,4,6-cycloheptatrien-1-one;
2-hydroxy-4-methyl-2,4,6-cycloheptatrien-1- -one;
2-hydroxy-4-dimethylethyl-2,4,6-cycloheptatrien-1-one; and
2-hydroxy-7-(hexloxymethyl)-2,4,6-cycloheptatrien-1-one, and
combinations thereof.
[0044] It will be understood that some of the above compounds may
exist in the form of salts. In such cases, the compounds may be
ionized and accompanied by a pharmaceutically acceptable anion or
cation as appropriate. Most commonly, a cation is a monovalent
material such as sodium, potassium or ammonium, but it can also be
a multivalent cation in combination with a pharmaceutically
acceptable monovalent anion, for example calcium with a chloride,
bromide, iodide, hydroxyl, nitrate, sulfonate, acetate, tartate,
oxalate, succinate, palmoate, or the like anion; magnesium with
such anions; zinc with such anions or the like.
[0045] The term "oral care composition" is meant to include
products, which are retained in the oral cavity for a sufficient
time to contact the dental surfaces and/or oral mucosal tissues and
exhibit the desired oral activity. The term "oral care effective
amount" as used herein is meant to be an amount of at least one
tropolone compound, sufficient to prevent or treat diseases or
conditions of the oral cavity, or to significantly eliminate or at
least suppress the presence of undesirable microorganisms in the
oral cavity, without causing side effects within the scope of sound
medical and dental judgment. The oral care effective amount of the
tropolone compounds of the present invention may vary with the
particular condition (e.g., to treat disease of the oral cavity or
malodor) being treated, the age and physical condition of the
patient being treated, the severity of the condition, the duration
of treatment, the nature of concurrent therapy, the specific form
(i.e., salt) of the tropolone compound employed, and the particular
carrier from which the tropolone compound is applied.
[0046] The concentration of the tropolone compounds in the oral
care composition of the present invention depends on the type of
composition (e.g., toothpaste, mouthwash and rinse, lozenge, gum,
etc.) used to apply the tropolone compounds to the gingival/mucosal
tissue and/or teeth, due to differences in efficiency of the
compositions contacting the tissue and teeth and due also to the
amount of the composition generally used. The concentration may
also depend on the diseases or conditions being treated.
[0047] In a preferred embodiment, the oral care compositions of the
present invention can include from about 0.001% to 10.0% by weight
based on the total weight of the oral care composition, preferably
from about 0.01% to 5.0% by weight, and more preferably from about
0.1% to 2.0% by weight of the tropolone compounds of the present
invention with the remainder of the formulation being the essential
oils, the carrier and other materials known in the art as oral care
composition components. Such additional components may include
buffers, surfactants, solubilizers, preservatives, emulsifying
agents, isotonizers, stabilizers, pH adjusting agents, sweeteners,
coloring agents, and the like.
[0048] The oral care composition of the present invention contains
an antimicrobial effective amount of an antimicrobial compound
having a structure of Formula (I) in combination with one or more
antimicrobially-effective essential oils as the active components.
Such antimicrobially-effective essential oils may include thymol,
menthol, methyl salicylate (wintergreen oil), eucalyptol,
carvacrol, camphor, anethole, carvone, eugenol, isoeugenol,
limonene, osimen, n-decyl alcohol, citronel, a-salpineol, methyl
acetate, citronellyl acetate, methyl eugenol, cineol, linalool,
ethyl linalaol, safrola vanillin, spearmint oil, peppermint oil,
lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil,
pimento oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise
oil, bay oil, benzaldehyde, bergamot oil, bitter almond,
chlorothymol, cinnamic aldehyde, citronella oil, clove oil, coal
tar, eucalyptus oil, guaiacol, lavender oil, mustard oil, phenol,
phenyl salicylate, pine oil, pine needle oil, sassafras oil, spike
lavender oil, storax, thyme oil, tolu balsam, terpentine oil, clove
oil and the like. The composition generally takes the form of a
solution containing these components in water.
[0049] The admixture of the antimicrobial compounds of Formula (I)
and antimicrobial essential oils preferably those selected from the
group consisting of thymol, menthol, eucalyptol, methyl salicylate,
and combinations thereof, provides a synergistic antimicrobial
effect.
[0050] In the oral care compositions, the essential oils are used
in amounts effective to provide oral care including the elimination
or suppression of oral microorganisms in the oral cavity.
Generally, the essential oils may be in the oral care composition
of the present invention in an amount of from about 0.001% to 8.0%
by weight based on the total weight of the composition; preferably
in an amount of from about 0.004% to 3.0% by weight; and more
preferably in an amount of from about 0.007% to 2.0% by weight.
Amounts employed in the oral care compositions may vary depending
on the form of the composition may be readily ascertained by those
skilled in the art. The compositions of the present invention
generally contain thymol and/or one or more other essential oils.
Preferably, the additional essential oils are eucalyptol, menthol,
or methyl salicylate, or mixtures thereof. Most preferably, the
composition contains all four of these essential oils.
[0051] Thymol ((CH.sub.3).sub.2CHC.sub.6H.sub.3(CH.sub.3)OH;
isopropyl-m-cresol), also known by the chemical formula 5-methyl
2-(1-methylethyl) phenol, is an effective antimicrobial agent, and
is typically obtained from the essential oil of Thymus vulgaris
Labiatae and Monarda punctata Labiatae. Thymol is a white
crystalline powder with an aromatic odor and taste and is soluble
in organic solvents but only slightly soluble in deionized water.
Thymol may be in the oral care composition of this invention in an
amount of from about 0.001% to 2.0% by weight based on the total
weight of the composition; preferably in an amount of from about
0.01% to 0.6% by weight; and more preferably in an amount of from
about 0.02% to 0.5% by weight.
[0052] Menthol (CH.sub.3C.sub.6H.sub.9(C.sub.3H.sub.7)OH;
hexylhydroxythymol) also possesses antiseptic properties and
provides a cooling, tingling sensation. Menthol is isolated
principally from the oil of Mentha arvensis. In its commercial
form, menthol is available as L-menthol crystals obtained from a
process involving cooling of the oil. Fractional distillation of
peppermint oil, which usually contains from about 40% to about 65%
menthol represents another important source of menthol. Synthetic
sources of L-menthol are also available. Menthol may be in the oral
care composition of the present invention in an amount of from
about 0.001% to 2.0% by weight based on the total weight of the
composition; preferably in an amount of from about 0.01% to 0.7% by
weight; and more preferably in an amount of from about 0.01% to
0.6% by weight.
[0053] Eucalyptol (C.sub.10H.sub.18O; cineol), another essential
oil with antiseptic properties, is derived from the eucalyptus
tree. Eucalyptol is a terpene ether that provides a cooling, spicy
taste and antiseptic activity. Having a camphoraceous odor and
cooling taste, this essential oil is often combined with other
essential oils such as menthol in confection formulations to impart
medicinal effect. Combinations of menthol and eucalyptol are widely
used. Particularly preferred uses of the menthol-eucalyptol
combination include, according to the present invention,
dentifrices such as toothpastes or dental gels. Eucalyptol may be
in the oral care composition of the present invention in an amount
of from about 0.001% to 2.0% by weight based on the total weight of
the composition; preferably in an amount of from 0.005% to 0.5% by
weight; and more preferably in an amount of from about 0.007% to
0.4% by weight.
[0054] Methyl salicylate (C.sub.6H.sub.4OHCOOCH.sub.3), also known
as wintergreen oil, is the main ingredient in many essential oils,
constituting about 99% of oil of wintergreen (Gaultheria
procumbens) and sweet birch (Betula lenta). Methyl salicylate,
which has a distinctive refreshing aroma, is used widely in
mouthwashes, chewing gums and other oral and pharmaceutical
preparations. Methyl salycylate is capable of providing flavoring
and organoleptic flavor tones to the oral care composition together
in addition to its antimicrobial function. Methyl salicylate may be
in the oral care composition of the present invention in an amount
of from about 0.001% to 2.0% by weight based on the total weight of
the composition; preferably in an amount of from about 0.004% to
0.6% by weight; and more preferably in an amount of from about
0.01% to 0.6% by weight.
[0055] The oral care composition of the present invention may
contain the following essential oils in percentages by weight based
on the total weight of the oral care composition: (a) thymol from
about 0.001% to 2.0% by weight; (b) menthol from about 0.001% to
2.0% by weight; (c) eucalyptol from about 0.001% to 2.0% by weight;
and (d) methyl salicylate from about 0.001% to 2.0% by weight.
[0056] In a preferred embodiment of the oral care composition of
the present invention, the oral care composition may contain the
following essential oils in percentages by weight based on the
total weight of the oral care composition: (a) thymol from about
0.01% to 0.6% by weight; (b) menthol from about 0.01% to 0.7% by
weight; (c) eucalyptol from about 0.005% to 0.5% by weight; and (d)
methyl salicylate from about 0.004% to 0.6% by weight.
[0057] In a more preferred embodiment of the oral care composition
of the present invention, the oral care composition may contain the
following essential oils in percentages by weight based on the
total weight of the oral care composition: (a) thymol from about
0.02% to 0.5% by weight; (b) menthol from about 0.01% to 0.6% by
weight; (c) eucalyptol from about 0.007% to 0.4% by weight; and (d)
methyl salicylate from about 0.01% to 0.6% by weight.
[0058] The oral care compositions of the present invention
containing tropolone compounds of Formula (I), and thymol and/or at
least one other essential oil provides effective antimicrobial
activity. The oral care compositions may further comprise other
antimicrobial agents if desired. Such exemplary antimicrobial
agents include chlorhexidine, chitosan, triclosan,
cetylpyridiumchloride, domiphen bromide, and the like. The amount
of such antimicrobial agents employed in the composition of this
invention can be readily determined by those skilled in the art.
The carrier for the oral care compositions of the present
invention, and particularly for the essential oils containing
compositions, may be aqueous medium. The aqueous medium may be a
water-alcohol mixture, generally a water-ethanol or
water-1-propanol mixture. The ethanol content level can be from
about 0.01% to 70% by weight based on the total weight of the
composition to solubilize and deliver the antimicrobial agents and
to provide a clear, aesthetically attractive liquid medium. A
favorable amount of ethanol for enhancement of the organoleptic
cues of the oral care compositions, specifically mouthwash
compositions, may range from about 0.1% to 30% by weight, more
preferably from about 20% to 30% weight, although lesser amounts
may be used if desired. Alternatively, the aqueous medium is
water.
[0059] The oral care compositions may be selected, for example,
from the group consisting of mouthwashes or rinses, toothpastes,
tooth powders, dental creams, dental flosses, liquids, gels,
chewing gums, liquid center filled gums, mints, lozenges, oral film
forming dentifrices, orally consumable films and the like.
[0060] The oral care compositions of the present invention comprise
a pharmaceutically acceptable oral carrier, in an amount
appropriate to accommodate the other components of the formulation.
The term "pharmaceutically acceptable oral carrier" refers to a
vehicle capable of being mixed with the active components for
delivery to the intended target in an oral cavity, and which will
not cause harm to warm-blooded animals including humans. The oral
carriers further include those components of the composition that
are capable of being commingled without interaction in a manner
which would substantially reduce the composition's stability and/or
efficacy for oral care including preventing or treating diseases or
conditions of the oral cavity in warm-blooded animals including
humans, in accordance with the compositions and methods of the
present invention.
[0061] The pharmaceutically acceptable oral carriers of the oral
care compositions can include one or more compatible solid or
liquid filler diluents or encapsulating substances, which are
suitable for oral administration. The carriers or excipients of the
present invention may be in any form appropriate to the mode of
delivery, for example, solutions, colloidal dispersions, emulsions,
suspensions, rinses, gels, foams, powders, solids, and the like,
and can include the usual and conventional components of
toothpastes (including gels and gels for subgingivial application),
mouthwashes and rinses, mouth sprays, chewing gums, orally
consumable films and lozenges (including breath mints). Carriers
suitable for the preparation of compositions of the present
invention are well known in the art. Their selection will depend on
secondary considerations like taste cost, and shelf stability,
etc.
[0062] Types of carriers which may be included in the oral
compositions of the present invention are abrasives, fluoride ions,
thickening agents, humectants, flavoring and sweetening agents,
anticalculus agents, alkali metal bicarbonate salts, surfactants
including nonionic and amphoteric surfactants, and anionic
surfactants, and miscellaneous carriers such as water, titanium
dioxide, anti-inflammatory agents, and the like.
[0063] Preferred compositions of the present invention are
mouthwashes, rinses, and mouth sprays. Components of such
mouthwashes, rinses and mouth sprays typically include water being
present in an amount of from about 45% to 95% by weight, and one or
more of ethanol up to 70%, a humectant up to 50%, a surfactant from
about 0.01% to 7%, a flavoring agent from about 0.04% to 2%, a
sweetening agent from about 0.1% to 3%, and a coloring agent from
about 0.001% to 0.5%. Such mouthwashes, rinses and mouth sprays may
also include one or more of an anticaries agent from about 0.05% to
0.3% (e.g., fluoride ion), and an anticalculus agent from about
0.1% to 3%.
[0064] Other preferred compositions of the present invention are
dental solutions. Components of such dental solutions generally
include water from about 90% to 99% by weight based on the total
weight of the oral care composition, and one or more of a
preservative from about 0.01% to 0.5%, a thickening agent up to 5%,
a flavoring agent from about 0.1% to 3%, and a surfactant up to
5%.
[0065] Other preferred compositions of the present invention are
orally consumable films or thin strips. Orally consumable films
typically comprise a rapidly dissolvable non-self-adhering
polymer-based thin film vehicle. Such compositions are typically
administered to the oral cavity where they rapidly dissolve upon
contact with saliva and provide rapid delivery of the active
ingredients. LISTERINE.RTM. POCKETPAKS.TM. brand oral care strip
products made by PFIZER, Inc. of Morris Plains, N.J. are perhaps
the most successful examples of an edible film compositions
effective in delivering therapeutic agents particularly
antimicrobial agents in the form of LISTERINE.RTM. essential oils
to the oral cavity. Components of such compositions generally
include water in an amount up to 75% by weight, a water soluble
film forming polymer including, but not limited to, pullulan, in an
amount of up to 25%, a flavoring agent in an amount of from about
0.01% to 10%, a surfactant in an amount up to 5%, and optionally,
copper salts in an amount of from about 0.01% to 5%.
[0066] Other preferred compositions of the present invention are in
the form of dentifrices such as toothpastes, tooth gels, and tooth
powders. Components of such toothpaste, and tooth gels generally
include one or more of a dental abrasive, generally from about 10%
to 50% by weight, a surfactant such as anionic, nonionic, or
zwitterionic detergent from about 0.5% to 10%, a thickening agent
from about 0.1% to 5%, a humectant from about 10% to 55%, a
flavoring agent from about 0.04% to 2%, a sweetening agent from
about 0.1% to 3%, a coloring agent from 0.01% to 0.5%, and water
from about 2% to 45%. Such toothpastes or tooth gels may also
include one or more of an anticaries agent from about 0.05% to 0.3%
(e.g., fluoride ion), and an anticalculus agent from about 0.1% to
13%. The liquids and solids are proportioned to form a creamy or
gelled mass, which is extrudable from a pressurized container or
from a collapsible tube. Tooth powders, of course, contain
substantially all non-liquid components.
[0067] Other preferred compositions of the present invention are in
the form of microcaps or more commonly known as gel beads, which
generally comprise a flavorant in an amount of from about 0.1% to
10% by weight, a lipophilic filler in an amount of from about 1% to
60%, an emulsifier in an amount of from about 0.1% to 5% and a
sweetening agent in an amount of from about 0.01% to 3%.
[0068] Chewing gum compositions typically include one or more of
gum base from about 50% to 99% by weight, a flavoring agent from
about 0.4% to 2% and a sweetening agent from about 0.01% to 5%.
[0069] The term "lozenge" as used herein includes: breath mints,
troches, pastilles, microcapsules, and fast-dissolving solid forms
including freeze dried forms (cakes, wafers, thin films, and
tablets) and fast dissolving solid forms including compressed
tablets. The term "fast dissolving solid form" as used herein means
that the solid dosage form dissolves in less than about 60 seconds,
preferably less than about 15 seconds, more preferably less than
about 5 seconds, after placing the solid dosage form in the oral
cavity. Lozenges include discoid shaped solids comprising a
therapeutic agent in a flavored base. The base may be a hard sugar
candy, glycerinated gelatin, or combination of sugar with
sufficient mucilage to give it form. Lozenge compositions
(compressed tablet type) typically include one or more fillers
(compressible sugar), flavoring agents and lubricants.
[0070] Surface active agents (surfactants) can be employed in the
composition of the present invention. They are organic materials
which aid in the complete dispersion of the components including
the active agents and flavoring oils throughout the solution as
well as dispersing the preparation throughout the oral cavity and
enable the compositions to provide a clear, uniform appearance that
is aesthetically more appealing. Preferably, the surfactant used in
the compositions of the present invention is a non-ionic surfactant
or anionic surfactant employed in an amount sufficient to help
solubilize the active components. By sufficient amount it is meant
that the surfactant is present in an amount that effectively
assists in the solubilization and delivery system kinetics of the
tropolone compounds and the essential oils.
[0071] Additional components may be added as known by those skilled
in the art. For example, acidic preservatives such as sorbic or
benzoic acid may be added to reduce pH levels. Buffer systems may
be necessary to control the pH of the composition at optimal
levels. This is generally accomplished through the addition of a
weak acid and its salt or a weak base and its salt. Useful systems
have been found to be sodium benzoate and benzoic acid in amounts
of from about 0.01% to 4.0% by weight, and sodium citrate and
citric acid in amounts of from about 0.001% to 0.2% by weight.
Preferably, the buffers are incorporated in amounts that maintain
the pH at levels of from about 3.5 to 9.0, and more preferably from
about 4.0 to 7.0.
[0072] In another embodiment of the present invention, there is
provided a method of treating or preventing diseases or conditions
of the oral cavity in warm-blooded animals including humans, by
applying an oral care effective amount of the oral care composition
of the present invention to the oral cavity. The oral care
effective amount of the oral care compositions of the present
invention is preferably applied to the mucosal tissue of the oral
cavity, to the gingival tissue of the oral cavity, and/or surface
of the teeth, for the treatment or prevention of the
above-mentioned diseases or conditions of the oral cavity, in one
or more conventional ways. For example, the gingival or mucosal
tissue may be rinsed with a solution (e.g., mouthwash, rinse)
containing the composition of the present invention; if a
dentifrice (e.g., toothpaste, tooth gel, or tooth powder) is
employed, the gingival/mucosal tissue or teeth may be bathed in the
liquid and/or lather generated by brushing the teeth; etc., for a
sufficient time, preferably from about 10 seconds to 10 minutes,
more preferably from about 30 seconds to 60 seconds.
[0073] The method of the present invention generally further
involves expectoration of most of the composition following such
contact. The frequency of such contact is preferably from about
once a week to about four times per day, more preferably from about
3 times per week to three times per day, even more preferably once
per day to twice per day. The period of such treatment typically
ranges from about one day to a lifetime. For particular diseases or
conditions of the oral cavity the duration of treatment depends on
the severity of the oral disease or condition being treated, the
particular delivery form utilized and the patient's response to
treatment. If the delivery to the periodontal pockets is desirable,
such as with the treatment of periodontal disease, a mouthwash or
rinse can be delivered to the periodontal pocket using a syringe or
a water injection device, for example. After irrigating, the
subject can swish the wash in the mouth to also cover the dorsal
portion of the tongue and other gingival/mucosal surfaces. In
addition to toothpaste, non-abrasive gel, tooth gel, etc., can be
brushed onto the tongue surface and other gingival and mucosal
tissues of the oral cavity.
[0074] Other non-limiting examples include chewing gum that
contains the composition of the present invention, chewing or
sucking on a breath tablet or lozenge. Preferred methods of
applying the oral care compositions of the present invention to the
gingival/mucosal tissue and/or teeth include rinsing with a
mouthwash or rinse solution and brushing with a dentifrice. Other
methods of applying the present composition to the gingival/mucosal
tissue and surfaces of the teeth are apparent to those skilled in
the art.
[0075] The present substituted tropolone compounds of Formula (I)
employed in the present invention may be prepared from readily
available starting materials using the following general methods
and procedures. It will be understood that where typical or
preferred process conditions (i.e. reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions may also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvents used, however such reaction conditions may be
determined by one of ordinary skill in the art through routine
optimization procedures. 3
[0076] Compounds of Formula (I) can be prepared as shown in Scheme
1 by reacting dichloroacetyl chloride with an R.sub.2-substituted
cyclopentadiene compound in the presence of a base such as
triethylamine to yield a cycloadduct of Formula (III). The
cycloadduct of Formula (III) is then treated with an acid such as
acetic acid and a base such as triethylamine to yield the final
desired product, a 4-alkyltropolone compound. When R.sub.2 is
isopropyl the resulting compound is hinokitiol which is used as a
starting material in Scheme 2. 4
[0077] Compounds of Formula (I) can further be prepared as shown in
Scheme 2 by treating hinokitiol with a carbonyl compound
(R.sub.6.dbd.O, wherein R.sub.6 is an alkyl group) such as
formaldehyde, acetaldehyde, proprionaldehyde, butyraldehyde, and
the like, in the presence of a base such as potassium hydroxide,
and thereafter adding an acid such as hydrochloric acid to yield a
4-isopropyl-7-hydroxyalkyltropolone compound. The
4-isopropyl-7-hydroxyalkyltropolone compound is then treated with a
chlorinating agent such as SOCl.sub.2 in the presence of a base
such as pyridine to yield a 4-isopropyl-7-chloroalkyltropolone
compound. The 4-isopropyl-7-chloroalkyltropolone compound is
reacted with an alcohol (R.sub.7OH; wherein R.sub.7 is an alkyl
group) such as methanol, ethanol, propanol, and the like, in the
presence of heat to yield the corresponding a
4-isopropyl-7-alkoxyalkyltropolone compound. 5
[0078] Compounds of Formula (I) can further be prepared as shown in
Scheme 3 by reacting 4-isopropyl-7-hydroxymethyltropolone with an
oxidizing agent such as MnO.sub.2 to yield
4-isopropyl-7-formyltropolone. The starting compound,
4-isopropyl-7-hydroxymethyltropolone, may be prepared by reacting
hinokitiol with formaldehyde in the presence of a base such as
potassium hydroxide, and thereafter treating the reaction with an
acid such as hydrochloric acid. 4-isopropyl-7-formyltropolone is
reacted with an alkylmagnesium bromide compound (R.sub.8MgBr;
wherein R.sub.8 is an alkyl group) and the reaction is quenched
with an acid such as hydrochloric acid to yield a
4-isopropyl-7-hydroxyalkyltropolone compound. The
4-isopropyl-7-hydroxyalkyltropolone compound is treated with a
reducing agent such as phosphorus, preferably red phosphorus, in
the presence of an acid such as acetic acid, whereupon as oxidizing
agent such as iodine is added to the reaction to yield a final
product of a 4-isopropyl-7-alkyltropolone compound.
[0079] The following examples are offered only to illustrate the
invention, and should not be interpreted as a limitation thereon.
For example, optimum reaction conditions may vary with the
particular reactants or solvents used, however such reaction
conditions may be determined by one of ordinary skill in the art
through routine optimization procedures.
EXAMPLE 1
Mouthwash Composition Containing Compounds of Formula (I) and
Essential Oils
[0080] A mouthwash composition was prepared having the following
components shown below in Table 1.
1 TABLE 1 Components % by weight 1) Thymol 0.064 2) Eucalyptol
0.092 3) Methyl Salicylate 0.060 4) Menthol 0.042 5) Alcohol, USP
21.6 6) Compound of Formula (I) 0.03 7) Flavoring Oil 0.085 8)
Poloxamer 407 0.15 9) Benzoic Acid 0.15 10) Sorbitol 20 11)
Saccharin 0.117 12) FD&C Green #3 0.0005 13) n-Propanol 0.5 14)
Water, USP QS to 100
[0081] The composition was prepared by adding the essential oils
(thymol, menthol, methyl salicylate and eucalyptol) and the
compound of Formula (I), flavoring oils, poloxamer 407 and benzoic
acid to alcohol followed by addition of 250 ml of water. Sorbitol,
saccharin, and the dye were added to the resulting mixture followed
by the addition of water to provide a 1000 ml sample of the
mouthwash composition.
EXAMPLE 2
[0082] 6
[0083] As illustrated in Scheme A, a solution comprising 25 mL of
triethylamine and 100 mL of a mixture of hexanes was added dropwise
to a solution containing 48.5 g of methylcyclopentadiene (prepared
from cracking methylcyclopentadiene dimer) and 22.5 g of
dichloroacetyl chloride in 200 mL of a mixture of hexanes at
0.degree. C. The mixture was stirred for about one hour and
thereafter poured into 150 mL of water at about 0.degree. C. The
layers were separated and the aqueous phase was extracted with two
75 mL portions of hexanes. The combined organic layers were washed
twice with water, then dried over Na.sub.2SO.sub.4 and concentrated
to yield an oil. Fractional distillation was performed under vacuum
to yield a cycloadduct of Formula (III), which was dissolved in 80
mL of acetone. The resulting solution was then added to a solution
containing 28.5 mL of acetic acid, 82.5 mL of triethylamine, 36 mL
of water and 100 mL of acetone. The mixture was refluxed under
nitrogen for about four hours. The acetone was removed from the
mixture under reduced pressure. An additional 100 mL of water was
added and then the solution was extracted three times each with 100
mL portions of ether. The combined organic extracts were washed
with water and dried over MgSO.sub.4. The final product,
4-methyltropolone, was recrystallized from hexanes to yield a white
solid.
EXAMPLE 3
Synthesis of 4-Isopropyl-7-methoxymethyltropolone
[0084] 7
[0085] As illustrated in Scheme B, a solution comprising 10 g of
hinokitiol and 18.8 mL of 25% aqueous KOH was heated to 60.degree.
C. under argon. Formaldehyde was added in 1 mL portions every 30
minutes until a total of 10 mL was added. The reaction mixture was
concentrated to a yellow paste and 300 mL of acetone was added. The
resulting yellow solid was collected and washed with acetone. The
solid was suspended in 250 mL in dichloromethane and 50 mL of 2.0M
HCl was added. The aqueous layer was washed with dichloromethane
and the combined organic layers were washed with water, and then
dried over Na.sub.2SO.sub.4. The solvent was removed under vacuum
leaving an oil which solidified upon trituration with petroleum
ether. An ice cold solution of 4.0 g of
4-isopropyl-7-hydroxymethyltropolone and 1.8 mL of pyridine in 100
mL of diethyl ether was vigorously stirred for two hours as a
solution of SOCl.sub.2 (2.5 mL) in 80 mL of ether was added
thereto. The resulting mixture was concentrated to yield a solid.
Boiling petroleum ether was added to the solid. The resulting
mixture was filtered and the filtrate was cooled to yield
4-isopropyl-7-chloromethyltropolone in the form of a solid. The
solid product was then refluxed in methanol under nitrogen for
about two hours and then concentrated to yield a golden oil. A
stream of N.sub.2 gas was passed over the oil until it solidified
to yield 4-isopropyl-7-methoxymethyltropolone in the form of a pale
yellow solid.
EXAMPLE 4
Synthesis of 4-Isopropyl-7-hexyltropolone
[0086] 8
[0087] As illustrated in Scheme C,
4-isopropyl-7-methoxymethyltropolone as produced in Example 2 was
oxidized in the presence of MnO.sub.2 to yield 0.85 g of
4-isopropyl-7-formyltropolone. 4-isopropyl-7-formyltropolone was
added to ether to yield a solution, which was stirred under N.sub.2
at 0.degree. C. 5 mL of a 2.0 M solution of pentylmagnesium bromide
was added to the solution via a syringe. The mixture was stirred
for about 45 minutes and then quenched with 20 mL of water. 10 mL
of 0.5 M HCl and 100 mL of ether was added to the mixture. The
layers were separated and the organic layer was dried over
Na.sub.2SO.sub.4. The solvent was removed and the resulting oil was
triturated with petroleum ether to yield
4-isopropyl-7-hydroxyhexyltropolone in the form of a yellow oil.
The oil product was mixed in 2 mL of water, 1 g of red phosphorus
and 15 mL of acetic acid. The mixture was stirred well and 1 g of
I.sub.2 was added. The reaction mixture was refluxed for about an
hour, and thereafter filtered. 150 mL of water was added the
filtrate. K.sub.2CO.sub.3 was added to the mixture to generate a
basic pH. The mixture was extracted with petroleum ether. The
organic layer was washed with Na.sub.2S.sub.2O.sub.3 and then with
water, and was dried over Na.sub.2SO.sub.4 to yield
4-isopropyl-7-hexyltropolone in the form of an oil.
[0088] The forgoing discussion discloses and describes merely
exemplary embodiments of the present invention. One skilled in the
art will readily recognize from such discussion, and from the
accompanying claims, that various changes, modifications, and
variations can be made therein without departing from the spirit
and scope of the invention as defined in the following claims.
* * * * *